The Northwestern University and the Ruth M. Rothstein CORE Center of the Cook County Health & Hospitals System Clinical Research Site (NC CRS) addresses the highest research priorities in HIV/AIDS research through retention and maintenance of the cohort, collection and repository storage of blood samples, and development and implementation of the unified science agenda. Through the leadership we provide and the data and blood samples we collect, the NC CRS actively contributes to core protocols and thematic sub- studies to characterize the long-term, natural and treated history of HIV infection in a representative cohort of people at substantial risk of becoming infected with the virus. We strictly adhere to good practice guidelines, established policies and procedures, and robust quality assurance and quality control measures to ensure the accuracy, reproducibility, and integrity of the clinical and laboratory data and blood samples. Scientific and administrative management provides both the flexibility and means to conduct multidisciplinary research projects as well as the resources to respond rapidly to recent scientific progress. For the past 35 years, we have maintained a comprehensive portfolio of biomedical and social science research on HIV and its related coinfections, comorbidities, and other complications. The diversity of the work makes possible a broad and multidisciplinary view of these high priority topics for understanding the basic biology of HIV, immune dysfunction and chronic inflammation, and genetic determinants. Scientific questions take full advantage of the strengths of the cohort, namely, its duration and the continuity of data and blood samples that timespan provides. Data and blood samples are available from people before and after infection, before and after beginning medications, or before and after the development of comorbidities or their complications. Productive relationships across the combined cohort, as well as other consortia and organizations, have coalesced around specific issues to advance scientific knowledge, the health of people, and policy development. By capitalizing on the expertise and unique resources of a multidisciplinary team of experts, we will build on our studies of genome sequence, patterns of gene and protein expression, and metabolite concentrations and changes (trans-omics dataset), along with information from people's medical records, to identify genes and pathways that play a role in disease and determine how they interact with HIV. Hierarchal models that predict the network behavior that gives rise to a phenotype will unravel the complexity of disease to provide novel and important insights into biological processes for testing or generating a set of hypotheses about disease mechanisms. During the next 7-year funding cycle, the NC CRS will continue support for the cohort and trans- omics for HIV/AIDS research that complements and extends the NIH Precision Medicine Initiative that connects genotype and phenotype and aligns with the NIH Big Data Initiative that supports innovative and transformative approaches to advance understanding of human health and disease.